PROJECT SUMMARY: Obesity is a growing health epidemic and is directly linked to the development of hypertension. Accumulating evidence from humans and animal models indicate that excessive central sympathetic nerve activity (SNA) plays a pathogenic role in obesity-associated hypertension. However, the central nervous system (CNS) networks and molecular mechanisms that lead to sustained elevations in SNA and arterial blood pressure during obesity remain unclear. There is mounting evidence that endoplasmic reticulum (ER) stress and activation of the transcription factor nuclear factor-?-B (NF?B) are involved in obesity. Our recently published observations, as well as exciting preliminary data, are in support of this and point to forebrain-hypothalamic networks as a culprit. Key findings, during diet-induced obesity in mice, have revealed robust ER stress and downstream activation of NF?B in the paraventricular nucleus of the hypothalamus (PVN) - a key CNS region involved in sympathetic and cardiovascular regulation. We also provide novel evidence that these pathophysiological alterations are mediated through an excitatory neural circuit involving the subfornical organ (SFO), a CNS circumventricular region located outside of the blood-brain-barrier that integrates circulating factors with the control of the autonomic nervous system. Using an approach that combines genomic interventions, neuroanatomical circuit analysis, chemogenetic manipulations, innovative imaging techniques, and integrative physiology, we will test the overall hypothesis that ER stress-induced NF?B activation in a forebrain-hypothalamic circuit involving the SFO and PVN mediates hypertension development during obesity. Using a murine model of obesity-induced hypertension, in Aim 1, we will dissect out the role of SFO excitatory signaling in PVN ER stress. Based on our evidence that ER stress intersects directly with NF?B activation, in Aim 2, we will interrogate ER stress-NF?B interactions in the PVN during obesity-related hypertension. In Aim 3, we will investigate the functional role of the SFO-PVN axis, as related to ER stress and NF?B activation, in mediating obesity-induced sympathetic overactivity and hypertension development. We will use an array of designer receptors engineered against designer drugs technology, intersectional viral techniques to target select neuron populations, transgenic mouse models, longitudinal in vivo bioluminescence imaging, molecular biology, state-of-the-art scanning electron microscopy techniques, and integrative cardiovascular/autonomic physiology to accomplish the proposed studies. Overall, this project will expand our knowledge of the underlying neurocircuitry and molecular mechanisms that contribute to hypertension development in obese conditions.